Osmium isotopic constraints on sulphide formation in the epithermal environment of magmatic-hydrothermal mineral deposits

In the magmatic-hydrothermal environment, fluids with similar metal concentrations and sources may yield contrasting mineral assemblages in successive stages of sulphide mineralization. These differences are linked to the physico-chemical conditions of the mineralizing fluids (e.g., T, pH, fS2, fO2) acquired during their interaction with country rocks and/or by mixing with groundwater. Here, we integrate petrography and osmium (Os) isotope (187Os/188Os) sulphide geochemistry, and discuss novel constraints on magmatic fluid-rock interaction and magmatic fluid-groundwater mixing that are deemed to govern sulphide deposition in magmatic-hydrothermal systems. We studied pyrite (FeS2) and enargite (Cu3AsS4) from the porphyry-related polymetallic Cerro de Pasco (14.54–14.41 Ma) and Colquijirca (10.83–10.56 Ma) epithermal deposits in the Central Andes, Peru. Sulphide mineralization is genetically associated with Miocene magmatism and includes breccia and replacement bodies of carbonate country rocks, and veins cutting the magmatic and sedimentary country rocks. At both deposits, pyrite is followed by enargite in the paragenesis. Pyrite has a radiogenic initial 187Os/188Os isotopic composition (187Os/188Osi-pyrite or Osi-pyrite = 0.80 to 1.45). Enargite (I) enclosing pyrite or filling in cracks in pyrite also has a radiogenic initial 187Os/188Os isotopic composition (Osi-enargite I = 0.56 to 1.24). Conversely, enargite (II) that formed on irregular surfaces on earlier pyrite has an unradiogenic 187Os/188Os isotopic composition (Osi-enargite II = 0.13 to 0.17). Our data show that the paragenetic evolution from pyrite to enargite records a sharp change in the osmium isotope composition within these sulphides. Pyrite and enargite (I) record radiogenic initial 187Os/188Os isotopic compositions, indicating interaction of magmatic hydrothermal fluids with the sedimentary country rocks. However, the unradiogenic initial 187Os/188Os isotopic composition of enargite (II) suggests that magmatic fluids with a mantle-like 187Os/188Os signature ascended from parental magmatic chambers to the epithermal environment without incorporation of crustal Os via fluid-rock interaction or mixing with groundwater. This difference may be due to the country rocks being altered during previous stages, with the radiogenic crustal Os signature being flushed by earlier magmatic pulses. Our findings imply that ore metals (i.e., Cu, Au) are magma-derived, whereas the Os isotopic composition of pyrite and some enargite in epithermal deposits may capture the signature of the interaction of magmatic fluids with country rock lithologies (e.g., the Eifelian black shale in the study area) and/or groundwater. Thus, the isotopic composition of the siderophile and chalcophile trace element Os in sulphides may act as a tracer of metal source, and degree of wall-rock interaction

Lack of Matrilin-2 Favors Liver Tumor Development via Erk1/2 and GSK-3 beta Pathways In Vivo

Matrilin-2 (Matn2) is a multidomain adaptor protein which plays a role in the assembly of extracellular matrix (ECM). It is produced by oval cells during stem cell-driven liver regeneration. In our study, the impact of Matn2 on hepatocarcinogenesis was investigated in Matn2(-/-) mice comparing them with wild-type (WT) mice in a diethylnitrosamine (DEN) model. The liver tissue was analyzed macroscopically, histologically and immunohistochemically, at protein level by Proteome Profiler Arrays and Western blot analysis. Matn2(-/-) mice exhibited higher susceptibility to hepatocarcinogenesis compared to wild-type mice. In the liver of Matn2(-/-) mice, spontaneous microscopic tumor foci were detected without DEN treatment. After 15 mu g/g body weight DEN treatment, the liver of Matn2(-/-) mice contained macroscopic tumors of both larger number and size than the WT liver. In contrast with the WT liver, spontaneous phosphorylation of EGFR, Erk1/2 GSK-3 alpha/beta and retinoblastoma protein (p-Rb), decrease in p21/CIP1 level, and increase in beta-Catenin protein expression were detected in Matn2(-/-) livers. Focal Ki-67 positivity of these samples provided additional support to our presumption that the lack of Matn2 drives the liver into a pro-proliferatory state, making it prone to tumor development. This enhanced proliferative capacity was further increased in the tumor nodules of DEN-treated Matn2(-/-) livers. Our study suggests that Matn2 functions as a tumor suppressor in hepatocarcinogenesis, and in this process activation of EGFR together with that of Erk1/2, as well as inactivation of GSK-3 beta, play strategic roles

Assessment of reward-related brain function after a single-dose of oxytocin in autism: A randomized controlled trial

Background Autism spectrum disorder (ASD) is characterized by difficulties in social communication and interaction, which have been related to atypical neural processing of rewards, especially in the social domain. Since intranasal oxytocin has been shown to modulate activation of the brain’s reward circuit, oxytocin might ameliorate the processing of social rewards in ASD and thus improve social difficulties. Methods In this randomized, double-blind, placebo-controlled, crossover fMRI study, we examined effects of a 24 IU dose of intranasal oxytocin on reward-related brain function in 37 men with ASD without intellectual impairment and 37 age- and IQ-matched control participants. Participants performed an incentive delay task that allows the investigation of neural activity associated with the anticipation and receipt of monetary and social rewards. Results Non-significant tests suggested that oxytocin did not influence neural processes related to the anticipation of social or monetary rewards in either group. Complementary Bayesian analyses indicated moderate evidence for a null model, relative to an alternative model. Our results are inconclusive regarding possible oxytocin effects on amygdala responsiveness to social rewards during reward consumption. There were no significant differences in reward-related brain function between the two groups under placebo. Conclusions Our results do not support the hypothesis that intranasal oxytocin generally enhances activation of reward-related neural circuits in men with and without ASD

Keratinocyte Growth Factor Induces Gene Expression Signature Associated with Suppression of Malignant Phenotype of Cutaneous Squamous Carcinoma Cells

Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes

Restoration of Podocyte Structure and Improvement of Chronic Renal Disease in Transgenic Mice Overexpressing Renin

Proteinuria is a major marker of the decline of renal function and an important risk factor of coronary heart disease. Elevated proteinuria is associated to the disruption of slit-diaphragm and loss of podocyte foot processes, structural alterations that are considered irreversible. The objective of the present study was to investigate whether proteinuria can be reversed and to identify the structural modifications and the gene/protein regulation associated to this reversal.We used a novel transgenic strain of mouse (RenTg) that overexpresses renin at a constant high level. At the age of 12-month, RenTg mice showed established lesions typical of chronic renal disease such as peri-vascular and periglomerular inflammation, glomerular ischemia, glomerulosclerosis, mesangial expansion and tubular dilation. Ultrastructural analysis indicated abnormal heterogeneity of basement membrane thickness and disappearance of podocyte foot processes. These structural alterations were accompanied by decreased expressions of proteins specific of podocyte (nephrin, podocin), or tubular epithelial cell (E-cadherin and megalin) integrity. In addition, since TGFbeta is considered the major pro-fibrotic agent in renal disease and since exogenous administration of BMP7 is reported to antagonize the TGFbeta-induced phenotype changes in kidney, we have screened the expressions of several genes belonging in the TGFbeta/BMP superfamily. We found that the endogenous inhibitors of BMPs such as noggin and Usag-1 were several-fold activated inhibiting the action of BMPs and thus reinforcing the deleterious action of TGFbeta.Treatment with an AT1 receptor antagonist, at dose that did not decrease arterial pressure, gradually reduced albuminuria. This decrease was accompanied by re-expression of podocin, nephrin, E-cadherin and megalin, and reappearance of podocyte foot processes. In addition, expressions of noggin and Usag-1 were markedly decreased, permitting thus activation of the beneficial action of BMPs.These findings show that proteinuria and alterations in the expression of proteins involved in the integrity and function of glomerular and renal epithelial phenotype are reversible events when the local action of angiotensin II is blocked, and provide hope that chronic renal disease can be efficiently treated

VITA-D: Cholecalciferol substitution in vitamin D deficient kidney transplant recipients: A randomized, placebo-controlled study to evaluate the post-transplant outcome

<p>Abstract</p> <p>Background</p> <p>Vitamin D does not only regulate calcium homeostasis but also plays an important role as an immune modulator. It influences the immune system through the induction of immune shifts and regulatory cells resulting in immunologic tolerance. As such, vitamin D is thought to exert beneficial effects within the transplant setting, especially in kidney transplant recipients, considering the high prevalence of vitamin D deficiency in kidney transplant recipients.</p> <p>Methods/Design</p> <p>The VITA-D study, a randomized, placebo-controlled, double-blind study with two parallel groups including a total of 200 kidney transplant recipients, is designed to investigate the immunomodulatory and renoprotective effects of cholecalciferol (vitamin D₃) within the transplant setting. Kidney transplant recipients found to have vitamin D deficiency defined as 25-hydroxyvitamin D₃< 50 nmol per liter will be randomly assigned to receive either oral cholecalciferol therapy or placebo and will be followed for one year. Cholecalciferol will be administered at a dose of 6800 International Units daily over a time period of one year.</p> <p>The objective is to evaluate the influence of vitamin D₃substitution in vitamin D deficient kidney transplant recipients on the post-transplant outcome. As a primary endpoint glomerular filtration rate calculated with the MDRD formula (modification of diet in renal disease) one year after kidney transplantation will be evaluated. Incidence of acute rejection episodes, and the number and severity of infections (analyzed by means of C-reactive protein) within the first year after transplantation will be monitored as well. As a secondary endpoint the influence of vitamin D₃on bone mineral density within the first year post-transplant will be assessed. Three DXA analyses will be performed, one within the first four weeks post-transplant, one five months and one twelve months after kidney transplantation.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00752401</p

Introduction to a Culturally Sensitive Measure of Well-Being: Combining Life Satisfaction and Interdependent Happiness Across 49 Different Cultures

How can one conclude that well-being is higher in country A than country B, when well-being is being measured according to the way people in country A think about well-being? We address this issue by proposing a new culturally sensitive method to comparing societal levels of well-being. We support our reasoning with data on life satisfaction and interdependent happiness focusing on individual and family, collected mostly from students, across forty-nine countries. We demonstrate that the relative idealization of the two types of well-being varies across cultural contexts and are associated with culturally different models of selfhood. Furthermore, we show that rankings of societal well-being based on life satisfaction tend to underestimate the contribution from interdependent happiness. We introduce a new culturally sensitive method for calculating societal well-being, and examine its construct validity by testing for associations with the experience of emotions and with individualism-collectivism. This new culturally sensitive approach represents a slight, yet important improvement in measuring well-being

Stability studies of cholesterol lowering statin drugs in aqueous samples using HPLC and LC-MS

International audienceIn this study, stability of statin drugs in different conditions, such as various pH, diverse solvents ratio, presence of UV, and sunlight have been investigated. Results suggest strong dependence of statins upon pH, potential environmental persistence towards sun light, and UV light degradation via singlet excited state obtained by excitation into the pi-pi* band. In acidic conditions interconversion between lactone and hydroxy acid forms in aqueous solutions at room temperature is retarded, while for the same sun-exposed samples are accelerated. Longer exposures lead to the degradation processes. Statin interconversion in water is much lower than in acetonitrile